The present invention concerns a process for the preparation of an isobenzofuran derivative. More particularly, the invention refers to a process for the preparation of 1-oxo-1,3-dihydro-5-isobenzofurancarboxylic acid.
1-Oxo-1,3-dihydro-5-isobenzofurancarboxylic acid, hereinbelow simply also referred to as 5-carboxyphthalide, represented by the formula A, 
is a useful intermediate in the preparation of several chemical compounds, particularly dyes, resins and drugs. In particular, 5-carboxyphthalide is an intermediate useful in the synthesis of citalopram, a well-known antidepressant drug, whose preparation using said intermediate is described in the International Patent Application WO 00023431 and in the corresponding Italian Patent Application IT1999 MI 0001724, whose contents are incorporated by reference herein.
It is known that 5-carboxyphthalide may be prepared by reduction of one of the carbonyl groups of trimellitic anhydride, which can occur by hydrogenation or, according to DE-2630927, by electrochemical reduction. This method has the drawback of giving a 5-carboxyphthalide containing, as a by-product, the 6 isomer in an amount which can reach 10%. An impurity which is present in such a percent cannot be accepted if 5-carboxyphthalide must be used as an intermediate in the preparation of drugs and, in such a case, it must be removed or strongly reduced to a value not higher than 0.1%. The removal of the 6 isomer occurs by several crystallizations which lower the yield in final product considerably.
It is also known that 5-carboxyphthalide may be prepared according to another method, described in U.S. Pat. No. 3,607,884, which comprises reacting terephthalic acid with formaldehyde in liquid sulfur trioxide (SO3). This synthesis must be carried out very cautiously whereby it is not suitable for the industrial scale-up owing to the problems connected to the use of liquid sulfur trioxide. More particularly, according to this method, it is needed to use small volumes of SO3 and to try to maintain a sufficient fluidity of the reaction mixture. Nevertheless, the reaction mass remains in any case thick and, therefore, involves a difficult handling for the recovery of the end product.
Furthermore, it is known (J. R. Blanc et al., J. Org. Chem. 1961, 26, 4731-4733) that isophthalic acid reacts with formaldehyde in oleum to give 3,3xe2x80x2,5,5xe2x80x2-tetracarbomethoxydiphenylmethane. According to this document, by heating at 119xc2x0 C. a mixture of 0.2 mol of isophthalic acid and 0.1 mol of 95% paraformaldehyde in 100 ml of oleum containing 20% of SO3, the 3,3xe2x80x2,5,5xe2x80x2-tetracarbomethoxydiphenylmethane is obtained in a 14% yield.
It is advisable to have a process that allows the synthesis of 5-carboxyphthalide with high yield and purity and easily controllable in the industrial scale.
Finally, it is known (L. R. S. Formey et al., J. Org. Chem. 1971, 36, 689-693) that a mixture of terephthalic acid, formaldehyde and oleum containing SO3, when heated at 150xc2x0 C. for 2 hours in a sealed tube, may give good conversion rates of terephthalic acid to 5-carboxyphthalide, the best conversion being achieved at a 60% SO3 concentration. However, according to this method, 5-carboxy phthalide is not isolated and said conversion rate is calculated after esterification with methanol and determination of the 5-carboxy phthalide methyl ester thus obtained by gas chromatography.
Reaction conditions like these, however, are not suitable for the industrial scale because pressure reactors and strong acidity conditions are required.
It has now surprisingly found that, by addition of terephthalic acid to fuming sulfuric acid (oleum) containing at least 20% of SO3, by subsequent addition of formaldehyde to the mixture and by heating, 5-carboxyphthalide is obtained in good yields and in a high degree of purity under easily controllable conditions, in open and however not pressurized reactors, and without any risk in handling the reaction mixtures.
Thus, the present invention provides, according to a method of simple execution, a process for the preparation of 5-carboxyphthalide of formula A, which comprises adding terephthalic acid of formula I 
to fuming sulfuric acid containing al least 20% of SO3, subsequently adding formaldehyde thereinto, heating the mixture at 120-160xc2x0 C. and isolating the obtained 5-carboxyphthalide.
According to a preferred embodiment of the process of the present invention, formaldehyde is used in one of its solid forms, currently in form of its precursor 1,3,5-trioxane of formula II 
in about equimolecular amounts in respect of the starting terephthalic acid, preferably corresponding to 2.5-3.2 mol of formaldehyde/mol of terephthalic acid.
The fuming sulfuric acid, which represents the reaction medium, also is the dehydrating agent which allows the direct transformation, in situ, of the 2-hydroxymethylterephthalic acid thus obtained of formula III 
into 5-carboxyphthalide of formula A.
In practice, terephthalic acid is added to fuming sulfuric acid, currently containing at least 20%, advantageously 22-33%, preferably 25-30% of SO3, then the mixture thus obtained is treated with 1,3,5-trioxane at a temperature of 30-35xc2x0 C. and subsequently heated at a temperature of 120-145xc2x0 C., preferably at 130-135xc2x0 C. Generally, it is sufficient to heat to 120xc2x0 C. so that the temperature of the reaction mixture increases by spontaneous exothermia up to 130-135xc2x0 C. Preferably, after having reached 120xc2x0 C., it is suitable to wait about 15 minutes in order to verify whether such exothermia has occured. In the negative, the temperature is brought to 130-145xc2x0 C. and, after a 2-5-hour heating at this temperature, there is formed compound III which concurrently dehydrates to give 5-carboxyphthalide. The preferably used amount of fuming sulfuric acid containing 25-30% in SO3 is 2-8 l/Kg of terephthalic acid, advantageously 2-6 l/Kg, preferably 3-6 l/Kg, particularly about 3 l/kg.
The advantage of the process of the present invention in comparison with known methods is that to give the 5-isomer of carboxyphthalide selectively. From the reaction mixture, which may contain some residual SO3, 5-carboxyphthalide is isolated according to methods known in the art.
Thus, for example, when the reaction is over, the mixture may be poured into ice, by anyhow controlling the exothermia of this operation, and the strong acidity of the medium may be neutralized with a base, preferably sodium hydroxide, carbonate or bicarbonate.
At the end of the reaction the mixture in sulfuric acid may also at first be diluted with glacial acetic acid and then treated with water. In such a case, advantageously, the mixture is diluted with glacial acetic acid in an amount of 200 ml per 100 g of terephthalic acid, by letting the temperature to rise to 20-25xc2x0 C. at the end of the addition. Successively the water is added and, under external cooling, the temperature may rise to 45xc2x0 C. Finally, the mixture is neutralized with a base, as set forth above.
In the isolation steps, during the addition of the base, it may be suitable to reach a pHxe2x89xa18, whereby the 5-carboxyphthalide is present in the solution as a salt, advantageously of an alkali metal, preferably of sodium, and to filter off the insoluble products whilst the 5-carboxyphthalide salt remains dissolved in the medium. In such a filtration it is suitable to use a neutral filter aid, for example Celite(copyright) or Dicalite(copyright). The 5-carboxyphthalide free acid may be easily recovered in good yields from the solution containing its salt by neutralization with an acid, for example with hydrochloric acid, and isolated in sufficiently pure form for its use as intermediate for the preparation of drugs. Practically, the 5-carboxyphthalide precipitates at acid pH at a value of about 3, preferably in the range of 1.8-3.0, and is isolated by simple filtration. In the isolation steps through the salt, preferably with an alkaline metal, it is suitable to maintain the pH value not higher than 8 in order to avoid the formation of by-products. Furthermore, during the treatment with the alkaline agent, it is suitable to control the pH changes when a value of about 5 is reached, because around this value it is possible that small additions of base involve considerable pH variations.
Alternatively, at the end of the reaction the mixture may be treated by dropping water thereinto, so that said water initially destroys any possible residual SO3 and then dilutes sulfuric acid progressively thus rendering the isolation of 5-carboxyphthalide easier. The addition of water, which produces exothermia, is preferably made at a temperature of 0-5xc2x0 C. However, the control of the temperature may be limited to the initial period of the addition of 10-15% of water (in respect of the used fuming sulfuric acid); afterwards, particular care are not necessary because the temperature of the mixture remains at about 20-25xc2x0 C. and, hence, it may be easily controlled. The 5-carboxyphthalide may be isolated by simple filtration, by washing with water, if necessary by triturating the obtained product in water.
The following examples illustrate the invention without, however, limiting it.